CN111269161B - Honokiol and sulforaphane conjugation and preparation method and application thereof - Google Patents
Honokiol and sulforaphane conjugation and preparation method and application thereof Download PDFInfo
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Abstract
本发明公开了一种厚朴酚与萝卜硫素拼接物及其制备方法和应用，所述厚朴酚与萝卜硫素拼接物包括：C25H29NO2S2(CT‑1)、C25H29NO4S2(CT‑2)、C25H29NO3S2(CT‑3)。本发明利用药物拼合原理，实现了厚朴酚与萝卜硫素拼接物(CT‑1，CT‑2，CT‑3)的首次合成。经生物学评价，其抗肿瘤效果显著优于厚朴酚和萝卜硫素，具有广谱的抗肿瘤活性和很强的成药性，是一个具有开发潜力的抗肿瘤化合物，也为新型抗肿瘤药物的开发提供了新的思路和途径。The invention discloses a magnolol and sulforaphane splicing compound and a preparation method and application thereof. The honokiol and sulforaphane splicing compound comprises: C 25 H 29 NO 2 S 2 (CT-1), C 25H29NO4S2 ( CT - 2 ), C25H29NO3S2 ( CT - 3 ). The present invention realizes the first synthesis of honokiol and sulforaphane splices (CT-1, CT-2, CT-3) by utilizing the principle of drug splicing. According to biological evaluation, its anti-tumor effect is significantly better than that of honokiol and sulforaphane. It has broad-spectrum anti-tumor activity and strong druggability. It is an anti-tumor compound with development potential and is also a new type of anti-tumor drug. The development provides new ideas and approaches.
Description
Technical Field
The invention relates to the technical field of medicines, and particularly relates to a magnolol and sulforaphane splice product and a preparation method and application thereof.
Background
Malignant tumors have become the second leading cause of death in humans and are one of the major diseases threatening human health at present. The natural medicinal resources of China are rich, active monomers are screened from the traditional Chinese medicines, and structural modification and reformation are carried out by using medicinal chemical means, so that the method has great significance for discovering novel antitumor medicaments.
Magnolol (Magnolol), also known as Magnolol, is one of the main components of traditional Chinese medicine magnolia officinalis and has moderate anti-tumor activity (Lin, s.y.; Liu, j.d.; Chang, h.c. Magnolol rendering of dried human colons and liver cells by in hibittingdnasynthesis and activating apoptosis [ J ]. j.cell Bio chem., 2002, 84, 532-. In recent years, the research on the antitumor mechanism of magnolol has become a hotspot of the research, and medicinal chemists can further enhance the antitumor activity of magnolol by carrying out structural modification on the magnolol (Tang, H.; Zhang, Y.; Li, D.discovery and synthesis of novel macromolecular derivatives with a pore anticancer activity in non-small cell lung cancer [ J ]. Eur J Med chem.,2018, 156, 190-.
Sulforaphane (Sulforaphane) is mainly present in crucifers and is an isothiocyanate compound which has been found to have the strongest cancer preventing and resisting ability in nature (Springer ta. traffic signals for lymphocyte diagnosis and leukocyte diagnosis: the multistep partner [ J ] Cell, 1994, 76, 301-314). Both have good medicinal value. Therefore, the two compounds are used as lead compounds to carry out structural modification and reformation and develop novel antitumor drugs, and have important theoretical significance and practical value.
Disclosure of Invention
In order to solve the problems in the prior art, the embodiment of the invention provides a magnolol and sulforaphane splicer and a preparation method and application thereof. The technical scheme is as follows:
in a first aspect, a magnolol and sulforaphane splice has the following structure:
in a second aspect, a preparation method of a magnolol and sulforaphane splice comprises the following steps:
dissolving magnolol in tetrahydrofuran, adding sodium hydride and 1, 2-dibromoethane, reacting for 3 hours at 60 ℃, adding water, extracting, drying an organic phase, concentrating, and separating to obtain a compound 2;
dissolving a compound 2 in N, N-dimethylformamide, adding sodium sulfide, reacting for 2 hours at 25 ℃, adjusting the pH value to 1, standing, filtering, collecting precipitates, dissolving the precipitates in the N, N-dimethylformamide, adding potassium carbonate and 4-bromo-1-butylamine, reacting for 12 hours at 25 ℃, concentrating a reaction solution, dissolving in tetrahydrofuran, adding triethylamine and carbon disulfide at 0 ℃, reacting for 2 hours at 25 ℃, adding water, extracting, drying an organic phase, concentrating, and separating to obtain a compound CT-1.
Further, the method further comprises:
dissolving the compound CT-1 in dichloromethane, adding m-chloroperoxybenzoic acid, reacting at 25 ℃ for 1 hour, adding a saturated aqueous solution of sodium bicarbonate, extracting, drying an organic phase, concentrating, and separating to obtain a compound CT-2 and a compound CT-3.
In a third aspect, the magnolol and sulforaphane conjugate of the first aspect is applied to preparation of an anticancer drug.
The technical scheme provided by the embodiment of the invention has the following beneficial effects: the invention realizes the first synthesis of the magnolol and sulforaphane splices (CT-1, CT-2 and CT-3) by utilizing the medicament splicing principle. According to biological evaluation, the antitumor effect of the compound is obviously superior to that of magnolol and sulforaphane, the compound has broad-spectrum antitumor activity and strong patent medicine property, is an antitumor compound with development potential, and provides a new thought and way for development of novel antitumor drugs.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, embodiments of the present invention will be described in detail with reference to the accompanying drawings.
Examples
Preparation of one, magnolol and sulforaphane splices
(1) 10mmol of magnolol (2.66g) is dissolved in 100mL of tetrahydrofuran, 40mmol of 60% sodium hydride and 40mmol of 1, 2-dibromoethane are added into the system to react at 60 ℃ for 3 hours, then 30mL of water is added into the system, 100mL of ethyl acetate is used for extraction, the organic phase obtained by extraction is dried by sodium sulfate and then concentrated, and finally the concentrated organic phase is separated by a silica gel column to obtain 6.5mmol of compound 2(2.4g) and light yellow liquid with the yield of 65%.
Compound 2: rf＝0.8(petroleum ether/EtOAc,10:1)；1H NMR(400MHz,Chloroform-d)δ7.14(dd,J＝6.5,2.2Hz,2H),7.11–7.02(m,2H),6.94(dd,J＝8.6,4.3Hz,2H),6.07(s,1H),6.04–5.87(m,2H),5.12–5.02(m,4H),4.22(t,J＝6.2Hz,2H),3.45(t,J＝6.2Hz,2H),3.39–3.30(m,4H)；13C NMR(100MHz,CDCl3)δ152.6,151.6,137.7,137.1,134.7,132.5,132.2,131.1,129.3,129.1,127.9,125.8,117.4,115.9,115.4,114.2,114.2,69.6,39.3,39.2,28.6；HRMS(ESI):m/z calcd for C20H21BrNaO2[M+Na]+:395.0623,found:395.0706.
(2) Dissolving 10mmol of compound 2(3.72g) in 100mL of N, N-dimethylformamide, adding 25mol of sodium sulfide, reacting at 25 ℃ for 2 hours, then adding 2mol/L of hydrochloric acid to adjust the pH to 1, standing, filtering, collecting precipitate, dissolving the precipitate in 50mL of N, N-dimethylformamide, adding 25mol of potassium carbonate and 25mmol of 4-bromo-1-butylamine, reacting at 25 ℃ for 12 hours, concentrating the reaction solution, dissolving the reaction solution in 30mL of tetrahydrofuran, adding 15mol of triethylamine and 5mol of carbon disulfide at 0 ℃, reacting at 25 ℃ for 2 hours, adding 30mL of water, extracting with 50mL of ethyl acetate, drying the obtained organic phase with sodium sulfate, concentrating, finally separating the concentrated organic phase with a silica gel column to obtain 6mmol, compound CT-1(2.6g), light yellow liquid, the yield was 60%.
Compound CT-1: rf＝0.2(petroleum ether/EtOAc,5:1)；1H NMR(400MHz,Chloroform-d)δ7.24–7.03(m,4H),6.98(dd,J＝8.2,4.7Hz,2H),6.01(dddd,J＝14.6,10.2,7.0,3.3Hz,2H),5.21–4.99(m,4H),4.20(t,J＝6.3Hz,2H),3.49(t,J＝6.3Hz,2H),3.41(t,J＝6.1Hz,4H),2.83(t,J＝6.3Hz,2H),2.48(t,J＝6.9Hz,2H),1.75–1.66(m,2H),1.66–1.56(m,2H)；13C NMR(100MHz,CDCl3)δ153.0,151.9,137.8,137.3,134.3,132.6,132.4,131.2,129.3,129.2,127.6,126.2,117.4,115.9,115.5,113.4,69.7,44.6,39.4,39.3,31.7,30.9,29.6,28.7,26.3；HRMS(ESI):m/z calcd for C25H29NNaO2S2[M+Na]+:462.1537,found:462.1770.
(3) 10mmol of compound CT-1(4.39g) was dissolved in 100mL of dichloromethane at 25 deg.C (room temperature), 11mol of m-chloroperoxybenzoic acid was added, reaction was carried out at 25 deg.C for 1 hour, then 30mL of saturated aqueous solution of sodium bicarbonate was added to the reaction solution, extraction was carried out with 50mL of dichloromethane, the organic phase obtained by the extraction was dried over sodium sulfate and concentrated, and finally the concentrated organic phase was separated with a silica gel column to obtain 3.9mmol of compound CT-2(1.8g), a pale yellow liquid with a yield of 39% and 6mol of compound CT-3(2.7g), a pale yellow liquid with a yield of 60%.
Compound CT-2: rf＝0.6(petroleum ether/EtOAc,1:1)；1H NMR(400MHz,Chloroform-d)δ7.22(dd,J＝8.4,2.3Hz,1H),7.13(dd,J＝8.0,2.2Hz,2H),7.01(d,J＝2.2Hz,1H),6.93(dd,J＝16.4,8.3Hz,2H),6.02–5.88(m,2H),5.16–5.01(m,4H),4.42(t,J＝5.1Hz,2H),3.45–3.34(m,6H),3.30(t,J＝5.2Hz,2H),2.66(t,J＝7.2Hz,2H),1.72–1.65(m,2H),1.60–1.52(m,2H)；13C NMR(100MHz,CDCl3)δ152.9,151.5,137.5,137.1,134.6,132.5,132.4,131.1,129.7,129.2,126.1,125.2,116.1,115.8,112.5,63.0,53.5,53.3,44.5,39.3,39.2,29.7,28.4,18.7；HRMS(ESI):m/z calcd for C25H29NNaO4S2[M+Na]+:494.1436,found:494.1854.
Compound CT-3: rf＝0.2(petroleum ether/EtOAc,1:2)；1H NMR(400MHz,Chloroform-d)δ7.20(dd,J＝8.4,2.3Hz,1H),7.16–7.07(m,2H),7.06–6.96(m,2H),6.91(d,J＝8.2Hz,1H),6.04–5.92(m,2H),5.17–5.04(m,4H),4.55–4.32(m,2H),3.49(t,J＝6.2Hz,2H),3.44–3.31(m,4H),3.13(ddd,J＝13.0,8.5,4.2Hz,1H),2.95(ddd,J＝13.9,5.5,3.4Hz,1H),2.71–2.57(m,1H),2.49(dt,J＝13.3,7.5Hz,1H),1.81–1.62(m,4H)；13C NMR(101MHz,CDCl3)δ153.1,151.8,137.7,137.2,134.5,132.3,132.1,131.1,129.3,129.2,127.4,125.8,116.7,116.0,115.6,113.4,61.7,51.6,51.4,44.5,39.4,39.3,28.8,20.2；HRMS(ESI):m/z calcd for C25H29NNaO3S2[M+Na]+:478.1487,found:478.2287.
Effect of the combination of magnolol and sulforaphane on proliferation of human lung cancer cell strain NCI-H460
1. Experimental Material
1.1 cell lines
Human lung cancer cell strain NCI-H460
1.2 medicinal materials, reagents and instruments
Fetal bovine serum (Hyclone), RPMI-1640 medium (Gibco), DMSO (sigma), CCK8 kit (Dalian Meilun Biotechnology Co., Ltd.), trypsin (Gibco Co., Ltd.), SpectraMax 190 microplate reader (Molecular Devices Co., Ltd.), low speed centrifuge (Kagaku scientific instruments Co., Ltd., Anhui), clean bench (Shanghai Boxun industries Ltd., medical facilities Co., Ltd.), inverted microscope (Miaodi Co., Ltd.).
2. Experimental methods
2.1 culturing NCI-H460 cells until they grow to logarithmic phase, i.e., they are digested with 0.25% trypsin, centrifuged at 1000 Xg for 5min, the cell pellet is resuspended in 1640 medium containing 10% FBS, and inoculated into 96-well culture plates at 5000/well density, then placed at 37 ℃ and 5% CO2And culturing overnight under saturated humidity conditions.
2.2 each group is provided with 6 multiple holes, each hole is added with medicine according to the following conditions, and then the culture is continued for 24 h.
Control group: namely, no medicine group is added.
The magnolol group: magnolol was added to a final concentration of 20 μ M.
CT-1 group: CT-1 was added to a final concentration of 20. mu.M.
CT-2 group: CT-2 was added to a final concentration of 20. mu.M.
CT-3 group: CT-3 was added to a final concentration of 20. mu.M.
After the cells are intervened for 24 hours, the CCK8 kit is used for detecting the influence of the medicine on the proliferation of the tumor cells. The specific operation is as follows: adding 10 mu L of CCK8 solution into each well, continuing culturing for 2h, measuring the absorbance (OD) value at the wavelength of 450nm of the microplate reader, and calculating the cell survival rate of other groups by taking the cell survival rate of the control group as 100%.
3. Results of the experiment
TABLE 1 Effect of magnolol and sulforaphane conjugate on proliferation of human lung cancer cell line NCI-H460
| Grouping | Inhibition ratio (%) |
| Control group | 0.00 |
| Magnolia officinalis phenol group | 1.20 |
| CT-1 group | 18.41 |
| CT-2 group | 70.34 |
| CT-3 group | 98.99 |
The results are shown in Table 1, and the magnolol and sulforaphane splices CT-1, CT-2 and CT-3 can obviously inhibit the proliferation of the human lung cancer cell NCI-H460, and the inhibition effect is obviously superior to that of a positive control medicament magnolol, wherein the antitumor activity of CT-3 is strongest.
Effect of CT-3 on proliferation of 7 human cancer cell lines
1. Experimental Material
1.1 cell lines
Human glioma cell line U251, human lung cancer cell line H1650, human liver cancer cell line HepG2, human breast cancer cell line MDA-MB-231, human gastric cancer cell line AGS, human colon cancer cell line LOVO and human ovarian cancer cell line OVCAR 3.
1.2 medicinal materials, reagents and instruments
Fetal bovine serum (Hyclone), RPMI-1640 medium (Gibco), DMSO (sigma), CCK8 kit (Dalian Meilun Biotechnology Co., Ltd.), trypsin (Gibco Co., Ltd.), SpectraMax 190 microplate reader (Molecular Devices Co., Ltd.), low speed centrifuge (Kagaku scientific instruments Co., Ltd., Anhui), clean bench (Shanghai Boxun industries Ltd., medical facilities Co., Ltd.), inverted microscope (Miaodi Co., Ltd.).
2. Experimental methods
2.1 culturing the above 7 kinds of cancer cells until they grow to logarithmic phase, digesting with 0.25% trypsin, centrifuging at 1000 Xg for 5min, resuspending the cell pellet in 1640 medium containing 10% FBS, inoculating to 96-well culture plate at 5000/well density, placing at 37 deg.C and 5% CO2And culturing overnight under saturated humidity conditions.
2.2 each group is provided with 6 multiple holes, each hole is added with medicine according to the following conditions, and then the culture is continued for 24 h.
Control group: namely, no medicine group is added.
Positive control group: the magnolol group and the sulforaphane group are respectively divided into 3 groups;
positive control group 1: magnolol was added to a final concentration of 5.0. mu.M.
Positive control group 2: magnolol was added to a final concentration of 10.0. mu.M.
Positive control group 3: magnolol was added to a final concentration of 20.0. mu.M.
Positive control group 4: sulforaphane was added to a final concentration of 5.0. mu.M.
Positive control group 5: sulforaphane was added to a final concentration of 10.0. mu.M.
Positive control group 6: sulforaphane was added to a final concentration of 20.0. mu.M.
CT-3 group: the CT-3 fractions were divided into 3 groups:
CT-3 group 1: CT-3 was added to a final concentration of 5.0. mu.M.
CT-3 group 2: CT-3 was added to a final concentration of 10.0. mu.M.
CT-3 group 3: CT-3 was added to a final concentration of 20.0. mu.M.
After the cells are intervened for 24 hours, the CCK8 kit is used for detecting the influence of the medicine on the proliferation of the tumor cells. The specific operation is as follows: adding 10 mu L of CCK8 solution into each well, continuing culturing for 2h, measuring the absorbance (OD) value at the wavelength of 450nm of the microplate reader, and calculating the cell survival rate of other groups by taking the cell survival rate of the control group as 100%.
3. Results of the experiment
TABLE 2 CT-3 median lethal dose (IC50) (μ M) for 7 human cancer cell lines
| Cell line | CT-3 | Magnolol | Sulforaphane |
| U251 | 7.75 | ＞45 | 22.47 |
| H1650 | 6.92 | ＞45 | 22.01 |
| HepG2 | 6.24 | ＞45 | 20.99 |
| MDA-MB-231 | 7.48 | ＞45 | 22.18 |
| AGS | 8.02 | ＞45 | 18.41 |
| LOVO | 5.10 | ＞45 | 18.52 |
| OVCAR3 | 5.34 | ＞45 | 18.44 |
As shown in Table 2, CT-3 significantly inhibited the proliferation of 7 human cancer cells, the IC of which50Is 5.10-8.02 mu M, which is obviously lower than that of more than 45 mu M of positive control medicament magnolol and 18.41-22.47 mu M of sulforaphane. The result shows that the anti-tumor activity of CT-3 is obviously higher than that of positive control medicament magnolol and sulforaphane.
Fourth, the effect of CT-3 on apoptosis of human lung cancer cell strain NCI-H460
1. Experimental Material
1.1 cell lines
Human lung cancer cell strain NCI-H460
1.2 medicinal materials, reagents and instruments
Fetal bovine serum (Hyclone), RPMI-1640 medium (Gibco), DMSO (sigma), CCK8 kit (Dalian Meilun Biotechnology Co., Ltd.), trypsin (Gibco Co., Ltd.), SpectraMax 190 microplate reader (Molecular Devices Co., Ltd.), low speed centrifuge (Hakka scientific instruments Co., Ltd., Anhui), ultra clean bench (Shanghai Boxun industries Ltd. medical facilities Co., Ltd.), inverted microscope (Macaudi Co., Ltd.), apoptosis detection kit and flow cytometer (BD Co., Ltd.).
2. Experimental methods
2.1 culture of NCI-H460 cells until logarithmic growth phase, i.e., digestion with 0.25% trypsin, 1000 Xg centrifugation for 5min, cell precipitation with 10% FBS 1640 medium regulation heavy suspension, 3.0X 105The density of each well is inoculated on a 96-well culture plate, and then the plate is placed at 37 ℃ and 5% CO2And culturing overnight under saturated humidity conditions.
2.2 each group is provided with 3 multiple holes, each hole is added with medicine according to the following conditions, and then the culture is continued for 24 h.
Control group: namely, no medicine group is added.
The magnolol group: magnolol was added to a final concentration of 10.0. mu.M.
Sulforaphane group: sulforaphane was added to a final concentration of 10.0. mu.M.
CT-3 group: CT-3 was added to a final concentration of 10.0. mu.M.
After the cells are intervened for 24 hours, the influence of CT-3 on the tumor cell apoptosis is detected by using an apoptosis detection kit and flow cytometry.
3. Results of the experiment
TABLE 3 Effect of CT-3 on apoptosis of human Lung cancer cell line NCI-H460
| Grouping | Apoptosis Rate (%) |
| Control group | 2.31 |
| Magnolia officinalis phenol group | 3.12 |
| Sulforaphane composition | 18.90 |
| CT-3 group | 73.82 |
The results are shown in Table 3, CT-3 can significantly induce apoptosis of human lung cancer cell NCI-H460, and the effect is obviously superior to that of positive control medicament magnolol and sulforaphane.
Effect of CT-3 on proliferation of human colon cancer cell line SW480
1. Experimental Material
1.1 cell lines
Human colon cancer cell strain SW480
1.2 medicinal materials, reagents and instruments
Fetal bovine serum (Hyclone), RPMI-1640 medium (Gibco), DMSO (sigma), CCK8 kit (Dalian Meilun Biotechnology Co., Ltd.), trypsin (Gibco Co., Ltd.), SpectraMax 190 microplate reader (Molecular Devices Co., Ltd.), low speed centrifuge (Hakka scientific instruments Co., Ltd., Anhui), ultra clean bench (Shanghai Boxun industries Ltd. medical facilities Co., Ltd.), inverted microscope (Macaudi Co., Ltd.), apoptosis detection kit and flow cytometer (BD Co., Ltd.).
2. Experimental methods
2.1 culture of SW480 cells until they grow to logarithmic phase, i.e., digestion with 0.25% trypsin, centrifugation at 1000 Xg for 5min, resuspension of the cell pellet in 1640 medium containing 10% FBS, 3.0X 105The density of each well was inoculated into 6-well culture plates, which were then incubated at 37 ℃ with 5% CO2And culturing overnight under saturated humidity conditions.
2.2 each group is provided with 3 multiple holes, each hole is added with medicine according to the following conditions, and then the culture is continued for 24 h.
Control group: namely, no medicine group is added.
The magnolol group: magnolol was added to a final concentration of 10.0. mu.M.
Sulforaphane group: sulforaphane was added to a final concentration of 10.0. mu.M.
CT-3 group: CT-3 was added to a final concentration of 10.0. mu.M.
After the cells are intervened for 24 hours, the influence of CT-3 on the tumor cell apoptosis is detected by using an apoptosis detection kit and flow cytometry.
3. Results of the experiment
TABLE 4 Effect of CT-3 on apoptosis of human colon cancer cell line SW480
| Grouping | Apoptosis Rate (%) |
| Control group | 3.11 |
| Magnolia officinalis phenol group | 4.02 |
| Sulforaphane composition | 19.99 |
| CT-3 group | 61.87 |
The results are shown in Table 4, CT-3 can obviously induce the apoptosis of the human colon cancer cell line SW480, and the effect is obviously superior to that of positive control medicament magnolol and sulforaphane.
Effects of CT-3 on apoptosis of normal cell strain LO2 of human liver
1. Experimental Material
1.1 cell lines
Human liver normal cell strain LO2
1.2 medicinal materials, reagents and instruments
Fetal bovine serum (Hyclone), RPMI-1640 medium (Gibco), DMSO (sigma), CCK8 kit (Dalian Meilun Biotechnology Co., Ltd.), trypsin (Gibco Co., Ltd.), SpectraMax 190 microplate reader (Molecular Devices Co., Ltd.), low speed centrifuge (Hakka scientific instruments Co., Ltd., Anhui), ultra clean bench (Shanghai Boxun industries Ltd. medical facilities Co., Ltd.), inverted microscope (Macaudi Co., Ltd.), apoptosis detection kit and flow cytometer (BD Co., Ltd.).
2. Experimental methods
2.1 culturing the above cancer cells until they grow to logarithmic phase, digesting with 0.25% trypsin, centrifuging at 1000 Xg for 5min, resuspending the cell pellet in 1640 medium containing 10% FBS, and 3.0X 105The density of each well was inoculated into 6-well cell culture plates, which were then incubated at 37 ℃ with 5% CO2And culturing overnight under saturated humidity conditions.
2.2 each group is provided with 3 multiple holes, each hole is added with medicine according to the following conditions, and then the culture is continued for 24 h.
Control group: namely, no medicine group is added.
The magnolol group: magnolol was added to a final concentration of 10.0. mu.M.
Sulforaphane group: sulforaphane was added to a final concentration of 10.0. mu.M.
CT-3 group: CT-3 was added to a final concentration of 10.0. mu.M.
After the cells are intervened for 24 hours, the influence of CT-3 on the tumor cell apoptosis is detected by using an apoptosis detection kit and flow cytometry.
3. Results of the experiment
TABLE 5 Effect of CT-3 on apoptosis of human Normal liver cell line LO2
The results are shown in Table 5, CT-3 has no significant induction effect on apoptosis of the normal cell strain LO2 of human liver, which indicates that CT-3 has no significant toxic and side effects on normal cells.
And (4) conclusion: CT-3 can inhibit the proliferation of various tumor cells, has antitumor activity obviously superior to that of a positive control medicament magnolol and sulforaphane, has no obvious toxic or side effect on normal cells, is an antitumor compound with development potential, and can be directly used for treating related diseases and preparing related medicaments.
The above-mentioned serial numbers of the embodiments of the present invention are merely for description and do not represent the merits of the embodiments.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents, improvements and the like that fall within the spirit and principle of the present invention are intended to be included therein.
Claims (4)
1. The magnolol and sulforaphane splicer is characterized by having the following structure:
2. a preparation method of a magnolol and sulforaphane spliced substance is characterized by comprising the following steps:
dissolving magnolol in tetrahydrofuran, adding sodium hydride and 1, 2-dibromoethane, reacting for 3 hours at 60 ℃, adding water, extracting, drying an organic phase, concentrating, and separating to obtain a compound 2;
dissolving a compound 2 in N, N-dimethylformamide, adding sodium sulfide, reacting for 2 hours at 25 ℃, adjusting the pH value to 1, standing, filtering, collecting precipitates, dissolving the precipitates in N, N-dimethylformamide, adding potassium carbonate and 4-bromo-1-butylamine, reacting for 12 hours at 25 ℃, concentrating a reaction solution, dissolving in tetrahydrofuran, adding triethylamine and carbon disulfide at 0 ℃, reacting for 2 hours at 25 ℃, adding water, extracting, drying an organic phase, concentrating, and separating to obtain a compound CT-1; wherein the structures of the compound 2 and the compound CT-1 are respectively
3. The method of claim 2, further comprising:
dissolving a compound CT-1 in dichloromethane, adding m-chloroperoxybenzoic acid, reacting for 1 hour at 25 ℃, adding a saturated aqueous solution of sodium bicarbonate, extracting, drying an organic phase, concentrating, and separating to obtain a compound CT-2 and a compound CT-3; wherein the structures of the compound CT-2 and the compound CT-3 are respectively
4. The use of the magnolol and sulforaphane conjugate of claim 1 in the preparation of an anticancer drug.
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| CN201911370139.4A CN111269161B (en) | 2019-12-26 | 2019-12-26 | Honokiol and sulforaphane conjugation and preparation method and application thereof |
| US17/803,393 US20240299556A1 (en) | 2019-12-26 | 2020-12-24 | Magnolol and Sulforaphane Conjgate, and Preparation Method and Use Thereof |
| PCT/CN2020/139058 WO2021129747A1 (en) | 2019-12-26 | 2020-12-24 | Magnolol and sulforaphane conjugate, and preparation method therefor |
| EP20908276.7A EP4083019A4 (en) | 2019-12-26 | 2020-12-24 | MAGNOLOL AND SULFORAPHANE CONJUGATE AND METHOD FOR THE PRODUCTION THEREOF |
| JP2022539765A JP2023508223A (en) | 2019-12-26 | 2020-12-24 | Magnolol and sulforaphane conjugate and method for producing the same |
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| CN113845410B (en) * | 2021-10-29 | 2023-09-29 | 深圳市真兴医药技术有限公司 | Synthesis method of magnolol derivative and intermediate thereof |
| CN114292222B (en) * | 2021-12-28 | 2024-02-02 | 深圳北京大学香港科技大学医学中心 | Magnolol derivative and preparation method and application thereof |
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| CN103315981A (en) * | 2013-05-10 | 2013-09-25 | 上海市肺科医院 | Application of biphenol and/or derivatives thereof in preparation of drugs for inhibiting cancer cell metastasis |
| CN103553888A (en) * | 2013-11-07 | 2014-02-05 | 蚌埠医学院 | Honokiol derivative and preparation method and application thereof in preparation of antitumor drugs |
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| US20060253100A1 (en) * | 2004-10-22 | 2006-11-09 | Medtronic, Inc. | Systems and Methods to Treat Pain Locally |
| BE1019431A3 (en) * | 2010-07-23 | 2012-07-03 | Auriga Internat | PROCESS FOR THE SYNTHESIS OF ISOTHIOCYANATES AND THEIR DERIVATIVES AND USES THEREOF |
| CN103127039A (en) * | 2011-11-22 | 2013-06-05 | 复旦大学 | Application of magnolol in preparation of antitumor drug |
| WO2013152313A1 (en) * | 2012-04-05 | 2013-10-10 | The Regents Of The University Of California | Compositions and methods for treating cancer and diseases and conditions responsive to growth factor inhibition |
| EP2664329A1 (en) * | 2012-05-15 | 2013-11-20 | F. Holzer GmbH | Ophthalmological vehicle system |
| WO2013179056A1 (en) * | 2012-06-01 | 2013-12-05 | Pharmagra Labs, Inc. | Sulforaphane isolation and purification |
| CN104710337B (en) * | 2015-02-12 | 2016-11-23 | 领思科技(大连)有限公司 | Isothiocyanate compounds and their applications |
| CN106924225A (en) * | 2015-12-31 | 2017-07-07 | 复旦大学 | Application of the magnolol in antineoplastic sensitizer is prepared |
| CN107098832B (en) * | 2016-02-23 | 2019-08-30 | 成都贝诺科成生物科技有限公司 | A kind of honokiol derivative and the preparation method and application thereof |
| CN111269161B (en) * | 2019-12-26 | 2022-03-08 | 深圳市真兴生物医药研究中心有限公司 | Honokiol and sulforaphane conjugation and preparation method and application thereof |
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| CN103315981A (en) * | 2013-05-10 | 2013-09-25 | 上海市肺科医院 | Application of biphenol and/or derivatives thereof in preparation of drugs for inhibiting cancer cell metastasis |
| CN103553888A (en) * | 2013-11-07 | 2014-02-05 | 蚌埠医学院 | Honokiol derivative and preparation method and application thereof in preparation of antitumor drugs |
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| WO2021129747A1 (en) | 2021-07-01 |
| EP4083019A4 (en) | 2024-02-21 |
| JP2023508223A (en) | 2023-03-01 |
| US20240299556A1 (en) | 2024-09-12 |
| CN111269161A (en) | 2020-06-12 |
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